Assessment and treatment of liver disease in Japanese haemophilia patients

Summary. We studied the prevalence of the hepatitis C virus (HCV), human immunodeficiency virus (HIV) and GB virus C or hepatitis G virus (GBV-C/HGV), and characteristics of infections in Japanese haemophilia patients. Haemophilia patients were highly infected with HCV (88.2%) because of frequent use of unheated blood concentrates. Analysis for HCV genotypes revealed characteristics of HCV infection in haemophilia patients. Japanese haemophilia patients were highly infected with rare genotypes in Japan: genotype 1a (26.5%), genotype 3 (14.5%) and genotype 4 (2.4%). HIV infection was observed in 32.3% of haemophilia patients. HCV quasispecies (clones) and direct sequencing were investigated in patients with a single HCV genotype in the hypervariable region 1 of HCV, which resulted in a high degree of diversity. This indicates that even a single genotype of HCV might have multiple origins. GBV-C/HGV infection was noted in 20.9% of Japanese haemophilia patients. Over 40 haemophilia patients with chronic hepatitis C have been treated with interferon alpha for 6 months at total doses of 480–720 million units. About 38% showed clearance of HCV RNA from serum. Six patients with HIV infection were included in the study and they did not show eradication of HCV from the serum. This might derive from that they had high serum HCV RNA titers and genotype 1a or 1b. Histologic assessment was performed in 36 haemophilia patients with HCV. No case showed a histologically normal liver. Hepatic fibrosis in the biopsy specimens was classified into five stages of fibrosis and compared with serum hepatic fibrosis markers. Serum hyaluronic acid mostly correlated with hepatic fibrosis (γ= 0.78, P < 0.0001) followed by type IV collagen (γ= 0.38, P < 0.05). This suggests that estimation of serum fibrosis markers might be substituted for liver biopsy in haemophilia patients.     

Serum hyaluronic acid reflects the effect of interferon treatment on hepatic fibrosis in patients with chronic hepatitis C

Changes in serum hyaluronic acid (HA) in 35 patients treated with interferon (IFN) were studied and the histological change in fibrosis was analysed. Serum HA levels and hepatitis C virus (HCV) RNA were followed from the start of therapy to 12 months after completion of treatment. Histological changes in pre- and post-treatment liver biopsies were assessed using a modified Knodell's scoring system. The serum levels of HA (r = 0.79; P<0.0001) correlated with the degree of fibrosis more closely than with that of amino terminal peptides of type III procollagen (PIIIP; r = 0.45; P<0.05) or type IV collagen (IV-C; r = 0.42; P<0.05). Only complete responders (CR) had a significant decrease in serum levels of HA and IV-C (P<0.05), in parallel with histological improvement (P<0.01). Neither partial responders (PR) nor non-responders (NR) had significant changes in histological scores and in serum levels of fibrotic markers. Significant differences were observed between CR and NR, both in HA levels (P<0.01) and PIIIP levels (P<0.05) 12 months after the cessation of treatment. These results suggest that serum HA is an indicator of the extent of fibrosis in chronic hepatitis C. Serial determinations of serum HA levels may be of use for monitoring the histological response of hepatic fibrosis to IFN treatment in chronic hepatitis C.     

Developmental changes in electroencephalogram for term and preterm infants using an autoregressive model

The purpose of the present study was to clarify the developmental changes of electroencephalogram (EEG) background activity in term and preterm infants that take place with increasing conceptional age (CA) through an autoregressive (AR) model. Polygraphical EEG recordings were obtained from 76 healthy term and preterm infants with a CA ranging between 31 and 40 weeks. Decreases in total power and component power of δ were noted with CA during burst activity (BA) in quiet sleep (QS) and during active sleep (AS). Increases in total power and component power of δ were noted with CA during interburst interval activity (IBIA) of QS. Regression analysis (RA) of the information amount (IA) indicated a negative correlation with increasing CA in AS and in the monopolar EEG tracings Fp1, C3, O1 and O2 in BA, and a positive correlation in O1 in IBIA. Regression analysis of the IA of δ indicated a negative correlation with increasing CA in AS and in Fp1, C3, O1 and O2 in BA, and a positive correlation in O1 in IBIA. Regression analysis of the IA of δ indicated a negative correlation with increasing CA in BA and AS. These results showed that the high voltage slow wave component changed to a low voltage slow one with development in AS and that BA was longer in duration and lower in power with increasing CA, while IBIA was shorter in duration and higher in power. In conclusion, significant developmental changes occur in all derivatives of AS. Even though the EEG of BA and IBIA change separately, they are followed by EEG of QS in a continuous pattern.     

Oral Tolerance Induced by Enterobacteria Altered the Process of Lymphocyte Recruitment to Intestinal Microvessels: Roles of Endothelial Cell Adhesion Molecules,TGF‐beta and Negative Regulators of TLR Signaling

Objective: Although enterobacteria are implicated in intestinal immune response, there has been no report on how intraluminal pathogens affect lymphocyte recruitment. The aim of this study was to determine how the presence of intestinal flora affects lymphocyte migration to intestine under physiological and lipopolysaccharide (LPS)‐induced inflammatory conditions. Methods: Interaction of T‐cells with ileal microvessels was monitored by using an intravital microscope in mice under germ‐free (GF) and specific pathogen‐free (SPF) conditions. LPS was administered into either the peritoneal cavity or duodenum before lymphocyte injection. Results: Adherence of T‐cells was greater in SPF than in GF mice, indicating that the presence of enterobacteria upregulated migration under physiological conditions. Intraperitoneally administered LPS significantly increased the adherence of T‐cells in both GF and SPF mice accompanied by the expression of adhesion molecules and proinflammatory cytokines. However, intraluminally administered LPS did not enhance the adherence of T‐cells in SPF mice. A significant induction of increase in mRNA expression of IRAK‐M, a negative regulator of TLR4 signaling, and transforming growth factor beta (TGF‐beta), a regulatory cytokine, was observed in SPF mice after luminal LPS treatment. Conclusions: Tolerance to intraluminally administered LPS in the lymphocyte recruitment process was induced by enterobacteria, possibly via the induction of IRAK‐M and TGF‐beta.     

Fatal liver failure in haemophiliacs with HIV-induced immunodeficiency: observation of six patients

We observed six cases of haemophiliacs with HIV-induced immunodeficiency who died from fatal liver failure despite the absence of evident cirrhosis. They all had the infection with hepatitis viruses (two patients with hepatitis B and D viruses and four patients with hepatitis C virus) and their CD4 counts were severely decreased. They were much younger than cirrhotic haemophiliacs without HIV. Their serum levels of hyaluronic acid and type IV collagen were lower than those in haemophiliacs with cirrhosis, and were normal. No patients had experienced symptoms or concomitant diseases characteristic of cirrhosis, such as ascites, jaundice, oesophageal/gastric varices or hepatocellular carcinoma, except for one case who had a history of mild ascites. The characteristics of this liver failure were different from liver failure resulting from cirrhosis caused by chronic hepatitis, which suggests liver failure that is specific to patients with immunodeficiency. This kind of liver failure can be a factor threatening survival in patients with HIV infection and with hepatitis virus co-infection in an immunodeficient state.     

Adequacy of Pacing Rate During Exercise in Rate Responsive Ventricular Pacing

Our objective was to determint; the adequate pacing rate during exercise in ventricular pacing by measuring exercise capacity, cardiac output, and sinus node activity. Eighteen patients with complete AV block and an implanted pacemaker underwent cardiopulmonary exercise tests under three randomized pacing rates: fixed rate pacing (VVJ) at 60 beats/min and ventricular rate-responsive pacing (VVIR) programmed to attain a heart rate of about 110 beats/min ar 130 beats/min (VVIR 110 and VVIR 130, respectively) at the end of exercise. Compared with VVI and VVIR 130, VVIR 110 was associated with an increased peak oxygen uptake(VVIR 110:20.3 ± 4.5 vs VVI: 16.9 ± 3.1; P < 0.01; and VVIR 130: 19.0 ± 4.1 mL/min per kg, respectively; P < 0.05) and a higher oxygen uptake at anaerobic threshold (15.3 ± 2.7, 12.7 ± 1.9; P < 0.01, and 14.6 ± 2.6 mL/min per kg; P < 0.05). The atrial rate during exercise expressed as a percentage of the expected maximal heart rate was lower in VVIR 110 than in VVI or VVIR 130 (VVIR 110: 75.9%± 14.6% vs VVI: 90.6%± 12.8%; P < 0.01; VVIR 110 vs VVIR 130: 89.1%± 23.1%; P < 0.05). There was no significant difference in cardiac output at peak exercise between VVIR 110 and VVIR 130. We conclude that a pacing rate for submaximal exercise of 110 beats/min may be preferable to that of 130 beats/min in respect to exercise capacity and sympathetic nerve activity.     

Unusually located lymphocutaneous nocardiosis caused by Nocardia brasiliensis

Summary We report a patient with primary lymphocutaneous Nocardia brasiliensis infection affecting the face and left arm. The mode of infection was via skin abrasions which occurred 2 weeks prior to the development of the skin lesions. Treatment with intravenous minocycline for 4 weeks resulted in a cure. We also review 12 previously reported Japanese cases of lymphocutaneous nocardiosis.     

Correlation of enhanced cell proliferation with decreased density of vitamin D receptor in parathyroid hyperplasia in chronic dialysis patients

Summary: The decreased density of the vitamin D receptor (VDR) plays an important role in the pathogenesis and progression of parathyroid hyperplasia in renal failure. In chronic dialysis patients, VDR density is less in nodular hyperplasia than in diffuse hyperplasia and the difference of cell proliferation has been also suggested by DNA analysis. to prove a more direct correlation between VDR density and cell proliferation, VDR density and proliferating cell nuclear antigen (PCNA) were detected in situ by immunohistochemistry in serial sections of surgically excised parathyroid glands from 10 chronic dialysis patients. Among 28 excised glands, 20 glands were nodular hyperplasia and eight glands were diffuse hyperplasia. Vitamin D receptor positive cells were much fewer in nodular hyperplasia (13.1 ± 4.8%) than in diffuse hyperplasia (383 ± 5.6%). In contrast, mean PCNA positive cell numbers per one 400 x field were much higher in nodular hyperplasia (2.0± 1.2) than in diffuse hyperplasia (0.1±0.2). These two parameters, simultaneously detected in the same area of the serial sections, showed strong negative correlation (r= -0.719, P <0.0001). Remarkable differences in VDR and PCNA were evident between nodules and the surrounding diffuse hyperplasia in the same section. These data suggest more direct relationship between the decrease of VDR density and parathyroid cell proliferation in chronic renal failure as a pathophysiological mechanism.